Dipyrromethanecarbinols have emerged as key intermediates in rational syntheses of porphyrinic macrocycles bearing meso-substituents in defined positions, including trans-A2B2-porphyrins (Rao et al., J. Org. Chem. 2000; 65: 1084, ABCD-porphyrins (Rao et al., J. Org. Chem. 2000; 65:7323), chlorins (Strachan et al., J. Org. Chem. 2000; 65: 3160; Balasubramanian et al., J. Org. Chem. 2000; 65: 7919), heteroatom-substituted trans-A2B2-porphyrins (Cho et al., J. Org. Chem. 1999; 64: 7890), and heteroatom-substituted corroles (Lee et al., Bull. Korean Chem. Soc. 2000; 21: 429). The application of dipyrromethanecarbinols depends on acid-catalyzed condensation conditions leading to the porphyrinic macrocycle that provide good yields while avoiding scrambling (rearrangement) that could give rise to a mixture of products. Due to the occurrence of severe scrambling, catalytic conditions traditionally used in syntheses of porphyrins from pyrrole+aldehyde (TFA or BF3-etherate with CH2Cl2 as solvent) are poorly suited for condensations involving dipyrromethanecarbinols. Following a lengthy survey (solvent, temperature, TFA or BF3-etherate) we found that changing the solvent to acetonitrile with use of TFA (30 mM) resulted in good yields of porphyrin (10-30%) while suppressing scrambling to below the limits of detection (Rao et al., J. Org. Chem. 2000; 65:7323).
While catalysis with TFA in acetonitrile has enabled synthesis of diverse porphyrinic macrocycles, some limitations remain. (1) Yields of porphyrin have been <40%, with 20-30% being most typical (Rao et al., J. Org. Chem. 2000; 65: 1084; Rao et al., J. Org. Chem. 2000; 65:7323; Strachan et al., J. Org. Chem. 2000; 65: 3160; Balasubramanian et al., J. Org. Chem. 2000; 65: 7919; Cho et al., J. Org. Chem. 1999; 64: 7890). (2) Scrambling has not been entirely suppressed in the case of alkyl-substituted dipyrromethanecarbinols (Rao et al., J. Org. Chem. 2000; 65:7323), and poor yields have been obtained with pyridyl substituted reactants (Gryko and Lindsey, J. Org. Chem. 2000; 65: 2249). (3) The shift to acetonitrile from CH2Cl2, required for the avoidance of scrambling, limits the range of substituents that can be used (due to low solubility in acetonitrile), and also complicates the isolation of the porphyrin. The higher polarity of acetonitrile causes a greater quantity of undesired polar pigments to elute through an initial pad of alumina, requiring an additional filtration through a pad of silica. A larger volume of CH2Cl2 is used in the filtration steps than would be the case if the reaction was performed in CH2Cl2. Attempts to evaporate the acetonitrile and re-dissolve the crude reaction mixture in CH2Cl2 results in significant losses of porphyrin due to trapping of porphyrin in poorly soluble reaction byproducts and residual DDQ. (4) The use of TFA in acetonitrile results in demetalation of some types of metalloporphyrins that are incorporated as substituents of dipyrromethane or dipyrromethane-carbinol species. Accordingly, there is a need for new synthetic methods in this area.